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eSymposia | Proteomics in Cell Biology and Disease


NPC Defects in Alzheimer’s Disease: Investigating NUP153, -93, and -214 and Transport Regulators NTF2, CAMK4, and IPO4 Mislocalization in Hippocampal Neurons


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

Description

NPC Defects in Alzheimer’s Disease: Investigating NUP153, -93, and -214 and Transport Regulators NTF2, CAMK4, and IPO4 Mislocalization in Hippocampal Neurons Authors *M. Tran1, M. GORAS1, D. BROKAW1, J. NOLZ1, E. DELVAUX1, D. MASTROENI1, P. COLEMAN1; Arizona State University-Banner Neurodegenerative Disease Research Center, Tempe, Arizona, USA. Abstract Alzheimer’s disease (AD) is a progressive, neurocognitive disorder characterized by memory dysfunction as well as the presence of neuropathological aberrations, namely amyloid plaques, and neurofibrillary tangles. However, AD neuropathology has been found to be a poor prognostic indicator and clinical trials targeting AD neuropathology have largely been unfruitful, necessitating new research into novel mechanisms of the underlying pathways mediating the cognitive decline. Eukaryotic cells rely on the movement of proteins between the nucleus and cytoplasm and, for cargo larger than a couple nanometers in diameter, transport is facilitated by the nuclear pore complex (NPC). NPC contain approximately 30 distinct nucleoporins (NUPs) which form a central channel with filaments extending into the nucleus and cytoplasm. Mutations in nucleoporin genes have been linked to various human diseases including nephrotic, cardiac, and neurodegenerative diseases. A recent study showed that mislocalization of nucleoporins from the nuclear membrane in AD may be directly interacting with soluble tau-p12 suggesting tau’s role in NPC deterioration and nuclear-cytoplasmic transport defects. However, this study only investigated four nucleoporins and is thus ill-equipped to make generalizable conclusions regarding global changes to the NPC that contribute to AD nuclear dysfunction and pathophysiology. Furthermore, there is a lack of research studying the effects of nuclear-cytoplasmic transporters and their relationship with cell function deterioration in AD. Mislocalization of NTF2, a protein that maintains the RAN gradient, could have widespread effects on a variety of cell processes on top of nuclear-cytoplasmic transport imbalance. In this study, we evaluate global changes to NPC and nuclear-cytoplasmic transporters in AD by analyzing gene expression from homogenate brain tissue and neuronal data. Three significantly differentially expressed NUPs (NUP-214, -93, -153), representing different parts of the NPC (cytoplasmic filaments, inner ring structure, nuclear basket), and NTF2, CAMK4, and IPO4 were selected from the significant results for further laboratory validation via immunohistochemistry and immunoblotting on human postmortem brain tissue. This laboratory research represents one of the first attempts to categorize differential changes throughout the NPC and transport regulators in AD. Bioinformatic analysis revealed widespread differential NUP and nuclear cytoplasmic transport gene expression across multiple brain regions in AD. These results were reflected in the immunohistochemistry and immunoblotting, which revealed quantity and localization changes of the selected NUPs and transporters in AD. Future studies will explore the hierarchical relationship between neuropathological hallmarks of AD and NPC and transport aberrations to better understand the etiology of impaired nucleocytoplasmic transport in neurodegeneration.

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